The present invention relates to novel pharmaceutical compositions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.
(1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and its antiviral use, particularly against HIV infections is described in European Patent Specification Number 0434450. The succinate salt of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in WO96/06844. The hemisulfate salt of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in WO98/52949.
(1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (also known as 1592U89) is currently under clinical investigation as an anti-HIV pharmaceutical agent. There exists a need for the compound to be prepared in solution form, for example for pediatric use.
Solutions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol are bitter-tasting and therefore require the addition of sweeteners and taste-maskers. However, formulation of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol in solution is difficult because materials containing a xe2x80x94COOH group present problems with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol compatibility. For example, glucose forms an adduct with the compound by replacing the methanol group on the cyclopentyl ring of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol. (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol has been found to be incompatible with sucrose (which degrades to glucose and fructose) as well as glucose.
Solutions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol containing sorbitol result in a color change and the formation of dark colored particulates at pH 4.5-6.5.
In addition, propylene glycol concentration appears to have an influence on color formation, with higher levels of propylene glycol (10%) causing color formation.
We have found that sorbitol or saccharin or a combination of sorbitol and saccharin are compatible with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and do not lead to the formation of adducts with it. In addition, lowering the pH to about 4.0 eliminates the color change and the formation of particulates. We have also found that combinations of fructose, acesulfame and saccharin are compatible with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol. In addition, we have found that abacavir is stable in pH ranges of about 2.0 to about 4.5 and about 6.6 to 7.5. Advantageously, the pH may be 3.8 to 4.5. We have also found that the addition of a metal chelator, for example citrate, improves the stability of abacavir in solution.
According to a first aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and sorbitol at a range of pH from about 2.0 to about 4.5, advantageously pH 4.0. In an alternative embodiment, there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.1. The pharmaceutical composition may comprise both sorbitol and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.1.
A further aspect of the invention includes compositions comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and sorbitol and/or saccharin at a pH range of about 6.6 to about 7.5, advantageously pH 7.0. Compositions at about pH 7 may include propylene glycol or other suitable solubilizer to improve solubility.
According to another aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and a sweetening agent compatible with said (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol at a pH range of about 2.0 to about 4.5.
In a further aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and fructose, acesulfame, and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.0. Alternatively, the compositions may be formulated at a pH range of about 6.6 to 7.5, advantageously pH 7.0.
According to a further aspect of the present invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, sorbitol, saccharin and citrate at a range of pH from about 2.0 to about 4.5. The citrate ion concentration may advantageously be in the range of about 0.01M to about 0.13M. Advantageously, sodium citrate and citric acid may be used.
The compositions of the present invention may also comprise one or more pharmaceutically acceptable organic solvents, for example, propylene glycol, polypropylene glycol, polyethylene glycol, and the like; pharmaceutically acceptable alcohols, for example ethanol or 2-(2-ethoxyethoxy)ethanol and the like; antioxidants, for example, edetate disodium, malic acid, fumaric acid, or sodium metabisulfite, and the like; pharmaceutically acceptable acids, for example, hydrochloric acid, acetic acid, citric acid, sulfuric acid, and the like; and oils or surfactants, and the like.
The compositions of the present invention may also comprise other pharmaceutically acceptable sweetening agents and/or flavoring agents, for example, aspartame, sucralose, and the like and/or cherry flavor, artificial banana flavor, caramel, chocolate mint flavor, grape flavor, wild cherry flavor, raspberry flavor, strawberry flavor, citrus flavor, orange flavor, pineapple flavor, citrus lime flavor, citrus cream flavor, cherry vanilla flavor, creme de menthe flavor and the like.
According to the present invention, any ester of hydroxybenzoate (parabens) or combination of such esters may be used, including methyl and propyl paraben and butyl and propyl paraben combinations. Sodium benzoate (0.02-0.5% w/v) or potassium sorbate (0.05-0.2% w/v) may be used as preservatives.
In a further aspect of the present invention, there is provided (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol compositions containing methyl paraben and propyl paraben. For oral solutions and suspensions, the range of methyl paraben concentration may be 0.15-0.2% (1.5 mg/mL to 2 mg/mL) and the range of propyl paraben concentration may be 0.01% to 0.02% (0.1 to 0.2 mg/mL).
According to a further aspect of the present invention, any suitable buffer may be used to provide a pH greater than 5.5. Advantageously, sodium citrate or phosphate may be used. To achieve a pH range of about 2.0 to about 4.5, advantageously citrate, fumarate, glutarate, malate, maleate, tartrate or acetate may be used.
Included in the invention are the pharmaceutically acceptable salts, esters, or salts of such esters of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, or any other compound which, upon administration of a safe and therapeutically effective amount of the compound to a human subject, is capable of providing (directly or indirectly) the antivirally active metabolite or residue thereof.
Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4 alkyl, or C1-4 alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
Preferred derivatives of 1592U89 are the mono-, di-, and tri-phosphate esters of (1R, 4S)-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]guanine (carbovir).
Examples of physiologically acceptable salts of 1592U89 and their physiologically acceptable derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+ (wherein X is C1-4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids. Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4+ and NX4+ (wherein X is a C1-4 alkyl group).
For therapeutic use, salts of 1592U89 will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
Preferred salts of 1592U89 are the succinate salt and the hemisulfate salt.
The formulations according to the invention may be presented in various forms adapted for direct oral administration including liquid forms, for example, syrups, suspensions, or solutions. The formulations, according to the invention, may include other pharmaceutically acceptable carriers as excipients conventionally used in such formulations.
The compositions of the present invention may be formulated using methods and techniques suitable for the compositions"" physical and chemical characteristics and that are commonly employed by persons skilled in the art of preparing oral dosage forms (Remington, The Science and Practice of Pharmacy, 19th ed., 1995).
The compositions according to the invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of HIV infections, such as nucleoside reverse transcriptase inhibitors for example zidovudine, zalcitabine, didanosine, stavudine, 5-chloro-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluorouridine, lamivudine, and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)1,3-oxathiolan-5-yl]cytosine; non-nucleoside reverse transcriptase inhibitors for example HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661, nevirapine (BI-RG-587), loviride (xcex1-APA), delavuridine (BHAP), phosphonoformic acid, (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1-(2H)-qinoxalinecarboxylate (HBY 1293); HIV protease inhibitors for example saquinavir, indinavir, ritonavir, nelfinavir, and 141W94; other anti-HIV agents for example soluble CD4; immune modulators for example interleukin II, erythropoetin, tucaresol; and interferons for example xcex1-interferon.
According to another aspect, the present invention provides a method for the treatment of an HIV infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a composition according to the invention.
Reference herein to treatment extends to prophylaxis as well as the treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi""s sarcoma, and AIDS dementia.
The present invention also provides the use of a composition, as hereinbefore described, in the manufacture of a medicament for the treatment and/or prophylaxis of HIV infections and associated clinical conditions hereinbefore described.
In general a suitable dose of 1592U89 for administration to a human for treatment of an HIV injection may be in the range of 0.1 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 90 mg per kilogram body weight per day and most preferably in the range 5 to 60 mg per kilogram body weight per day.
Unless otherwise indicated all weights of active ingredients are calculated in terms of the drug per se. In the case of a physiologically functional derivative of 1592U89 or a solvate of any thereof the figures would be increased proportionately. The desired dose may preferably be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 5 to 1000 mg, most preferably from 10 to 700 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the dose may be administered as a continuous infusion.
Pharmaceutical compositions according to the present invention may contain one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
The present invention may conveniently be presented as a pharmaceutical composition in a unit dosage form. A convenient unit dosage composition contains the active ingredients in amounts of from 50 mg to 3 g each, for example, 100 mg to 2 g.
The concentration of 1592U89 hemisulfate salt may be 1-90 mg/ml at a pH range of about 2.0 to about 4.5.
The unit dosage form may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product
Preferred unit dosage compositions are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
Pharmaceutical compositions are often prescribed to the patient in xe2x80x9cpatient packsxe2x80x9d containing the whole course of treatment in a single package, usually a blister pack or a foil pouch. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient""s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physicians instructions and, therefore, lead generally to more successful treatment.
It should be understood that in addition to the ingredients particularly mentioned above the compositions of this invention may include other agents conventional in the art, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
1592U89 may be prepared by the method described in European Patent Specification Number 0434450 or PCT Application No. GB95/00225 which are incorporated herein by reference hereto.
The succinate salt of 1592U89 may be prepared by the method described in PCT Application No. GB95/02014, which is incorporated herein by reference hereto.